The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
All publications and patent applications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
The mammalian immune system comprises innate and adaptive immune cells operating in concert to recognize and remove damaged, infected, or otherwise diseased cells and/or tissues. This is accomplished through a complex sequence of events using sensory pathways to identify affected tissues (typically via innate immune cells such as monocytes/macrophages, dendritic cells, and natural killer or NK cells) and effector cells and/or their products (typically T- and B-lymphocytes, antibodies, etc.) to not only eradicate targeted tissues but also form an exquisitely specific immunological memory against the offending agent.
Increasing knowledge of the molecular events surrounding immune activation has led to the creation of ever more active vaccines that in turn provide protection against an increasing array of pathogens. For example, early vaccine formulations have focused on stimulating host B-cells to produce protective antibodies, while more recent vaccine formulations attempt to target cancer cells for recognition by host CD8+ cytotoxic T cells and subsequent destruction. Conversely, other attempts aimed to induce tolerance via CD4+ T cell recognition of “self” or inert antigens to treat autoimmune diseases or allergic reactions. Notably, and common to most, if not all of the targeted responses of the immune system to an offending antigen are recognition events mediated between MHC-complexes on affected cells and T-cell receptors on specific T-cells in the cellular immune response, particularly CD8+ and CD4+ cells.
Human CD8+ T cell activation generally requires recognition of a tri-molecular complex of proteins on the surface of target cells composed of a classical MHC-I heavy chain (e.g. HLA-A, -B, or -C in man), a non-covalently bound β-2 microglobulin (β-2m) light chain, and a short peptide (typically 8-11 amino acids) that is derived from proteosomal degradation of cytoplasmic proteins. Like most cellular macromolecules, cytoplasmic proteins exhibit unique half-lives, and “older” proteins are degraded and turned over by the proteasome complex into short peptides. These peptides are transferred to the lumen of the ER by the TAP1/2 complex where they are loaded onto the classical MHC-I heavy chain/β-2m complexes and ‘quality controlled’ by accessory proteins like tapasin. Once appropriately loaded, these complexes traffic through the Golgi apparatus to the cell surface where they interact with T cell receptors (TCR) of circulating CD8+ T cells.
Unlike CD8+ T cells, CD4+ T cells recognize a tri-molecular complex of surface proteins composed of α and β chains of MHC-II (HLA-DR, DP, and DQ α and β loci in man) and bound peptides (typically 12-20 amino acids). Unlike MHC-I, MHC-II is significantly more restricted in its expression (e.g., limited to antigen presenting cells like monocytes/macrophages, dendritic cells, and B-cells) and MHC-II associated peptide epitopes are often derived from extracellular or endosomal sites and not the cytoplasm.
Despite many advances in creating antigen-specific protective immune responses against foreign or otherwise offending antigens through immunization, inhibition of undesired antigen specific immune responses remains a difficult task. This is particularly apparent in tissue transplantation where suppression of tissue rejection is generally limited to immunosuppressive therapy (e.g., via corticosteroids, mTOR and/or calcineurin inhibitors, etc.), antibody therapy, or bone marrow transplant. However, such therapies are often fraught with undesirable side effects and tend to only incompletely protect the allograft. In addition, use of immunosuppressive agents compromise the recipient's immune system, frequently with disastrous consequences. Therefore, success of allograft transplants most heavily relies on HLA-based tissue type matching.
Mechanistically, allograft rejection is predominantly effected by the recipient's CD8+ cytotoxic T cells via recognition of the grafted cells'/tissue's foreign MHC-I proteins. In addition, CD4+ T cells can also recognize allografts where they express foreign MHC class II (like HLA-DR). To complicate matters further, pre-existing serum antibodies specific for graft proteins can also lead to graft rejection. By some estimates, 1-10% of a recipient's T cells recognize and respond to allografts, destroying grafts within days to weeks in a peptide epitope-independent manner, while T cell antigen recognition of typical antigens is restricted by the host's particular haplotype of MHC-I or -II and specific for the bound peptide under normal immunological conditions (with antigen-specific T cell frequencies numbering many powers of ten less than their alloreactive counterparts in antigen naïve hosts). This intrinsic reactivity to foreign cells necessitates tissue matching between donors and recipients across the HLA loci (and in particular, HLA-A, HLA-B, and HLA-DR proteins) and is generally deemed critical to graft acceptance.
It should be appreciated that normal biological conditions exist where certain cells evade CD8+ T cell recognition, including neurons and an embryo's trophoblast cells during pregnancy (as recognition of the father's “alloantigens” would lead to destruction of the embryo). Altered expression or function of proteins required for MHC-I antigen processing/presentation is also noted in many varieties of cancer cells, which use this mechanism to avoid detection of cancer neo-antigens by CD8+ T cells, and in certain viral infections via expression of viral proteins like human herpesvirus 1 (HHV-1) ICP47, cytomegalovirus (CMV) unique short region proteins US2, US3, US6, and US11, etc.
Unfortunately, attempting to employ a similar strategy of inhibiting or otherwise decreasing a donor cells' MHC I expression is unlikely to provide a singular solution to allograft rejection due to the phenomenon of “missing-self recognition” by NK cells. For example, incomplete protection from allograft rejection via reduction of MHC-I expression in the transplant is seen in Kidney International, Vol. 62 (2002), pp. 290-300. In addition, NK cells, unlike CD8+ cytotoxic cells, can kill target cells producing insufficient levels of cell surface MHC-I without MHC restriction. NK cell activation is dependent on a complex and integrated balance of signals from both activating and inhibitory receptors on the cell surface, and because target cells expressing insufficient levels of MHC-I do not provide sufficient inhibitory signals through MHC-I expression, they are often destroyed. Due to the limited expression of MHC-II throughout the body and its specialized role in immune responses, a similar NK cell-based strategy for identification of cells that demonstrate altered or decreased MHC-II expression has not yet been identified and should be considered only for grafts which express HLA class II (e.g. hematopoietic stem cells).
In yet another known approach of preventing tissue rejection, recipient allo-activated regulatory T cells can be generated ex vivo and are then introduced into a recipient before transplantation. Donor antigen is introduced into the recipient after transplantation to boost recipient regulatory T cells as described in US20060292164A1. All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply. While such approach may circumvent at least some of the above problems, other difficulties still remain. Most notably, such method may still not overcome problems with tissues having HLA-type mismatch.
Thus, even though various approaches are known in the art to reduce allograft recognition and rejection, several drawbacks still remain. Therefore, there is still a need for compositions, cells, and methods to reduce allograft recognition and rejection.